Intermediates in the conversion of 11-ketodiosgenin to cortisone



United States Patent G 2,998,436 INTERMEDIATES IN THE CONVERSION OF ll-KETODIOSGENIN T 'CORTISONE Edward S. Rothman, Philadelphia, and Monroe E. Wall,

Oreland, Pa., assignors to the United States of America as represented by the Secretary of Agriculture No. Drawing. Filed Mar. 5, 1957, Ser. No. 644,184

5 Claims. (Cl. 260-39145) (Granted under Title 35, US. Code (1952), sec. 266) A non-exclusive, irrevocable, royalty-free license in the invention herein described, throughout the world for all purposes of the United States Government, with power to grant sublicenses for such purposes, is hereby 2,998,436 l atented Aug. 29, 1961 c ce The advantage of our process lies in the avoidance of these multiple, low-yielding steps.

Our invention will now be described with reference to granted to the Government of the United States of Amerthe following diagrams:

FLOW SHEET OF CHEMICAL TRANSFORMATION CH3 CH3 CH! 0H, CH8

0 of 0 0 v CH CH CH" ---v -----p -v AcO AcO R0 CHzOR --OR! 0 0 of CH CH CH v R==H VII R=HCO; R==H X R=R'=CH.5CO v1 R=HCO VIII R=HCO; R=OH O0 XI R=R=H Ix R=H; R=CHaCO ica. In co -pending patent applications Serial Numbers Inour process we degrade ll-keto diosgenin acetate, 566,737, filed February 20, 1956, now US. Patent 1, by a process well-known to those familiar with the art 2,830,986 and 644,183, filed March 5, 1957, now US. to the new compound 3B-acetoxy-5,l6-pregnadiene-11,20- Patent 2,899,428, steroidal sapogenins' gentrogenin and dione, II. It is neither desirable or necessary to isolate its C- diastereoisomer correllogenin were described intermediates in the course of this transformation of and were converted to the new steroidal sapogenin, 11- s-apogenin to pregnadiene. The product, isolated in keto diosgenin. When ll-keto diosgenin is converted to yield or better, is treated with alkaline hydrogen peroxide cortisone via ll-keto tigogenin, the advantages of its to selectively epoxidize only the 16-17 olefinic bond to olefinic functional group are wasted in so doing. It is form 3,8- acetoxy-loa,17a-epoxy-5-pregnene-11,20-dione, the purpose of the present disclosure to show that ll-keto 55 III, in 84% yield. The product is saponified in nearly diosgenin can be converted to cortisone via a new route 100% yield to 16oz,170t-6pOXy-3ot-hYdIOXY-S-Pl6gl16fl6- involving new intermediates in which full advantage of 11,20-dione, IV. Treatment of this material with hydrothe naturally occurring 3-hydroxy 5,6-olefinic functional bromic acid followed by Raney nickel debromination group system can be made. Among the advantages of produces 3,6,17a-dihydroxy-5-pregnene-11,20-dione, V, in the 3-hydroxy 5,6-olefinic system is the ease with which 70% yield for the two steps. This material is formylated it can be converted in a one step, high-yield Oppenauer at the (3-3 hydroxy group in 80% yield to give 3 8-foroxidation to the A -3 ketone system necessary for the moxy-l7a-hydroxy-5-pregnene-l1,20-di0ne, V1. Treatphysiological adrenal cortical hormone activity of cortiment of the formate with one molar equivalent of bromine: sone. This one step conversion contrasts with the multiwould be expected to saturate the 5,6-olefinic bond since, ple operations necessary in converting the 11-keto tigoin general, addition reactions are more rapid than subgenin derivative to the A -3 ketone system in the comstitution reactions. Surprisingly, this expected reaction mercial processes. These multiple operations involve of double bond saturation does not occur to any major; (1) oxidation to the saturated 3-ketone, (2) dibrominaextent. Instead substitution on the C-21 methyl, group tion at the 2 and 4 positions, (3) reaction with sodium occurs. Lowered yields are obtained if more, than one iodide to simultaneously metathetically replace the C-2 mole of bromine is added; therefore, excess bromine is,

bromine atom with an iodine atom and establish a A bond and (4) finally to reductively remove the iodine to be avoided. Treatment of the bromination product with sodium iodide followed by a subsequent, separate asasnse treatment with sodium or potassium acetate gives the diester, 21-acetoxy-3/3-formoxy-17a-hydroxy-5-pregnene- 11,20-dione, VII. Acetylation of this compound either by long refluxing with acetic anhydride or by 18-hour treatment at room temperature with an acetylation catalyst such as p-toluene sulfonic acid or perchloric acid gives 1711,21 diacetoxy 3,8 formoxy-S-pregnene-l1,20- dione, VIII. In the course of isolation some hydrolytic loss of formate sometimes occurs to form 17,21-diacetoxy-3B-hydroxy 5 pregnene 11,20 dione, IX, but this offers no disadvantage since both 3B-hydroxyl group and the 3,8-formoxyl group behave alike to the mildly alkaline aluminum isopropoxide Oppenauer reagent, and form the same 3-ketone. This Oppenauer oxidation product. of the 3-formate or of the 3-hydroxyl compound or of'their mixtures produces the known cortisone 17a,21-diacetate, X. All compounds preceding cortisone 17a,21-diacetate in this series of transformations are new compounds not previously described. Hydrolysis of cortisone diacetate produces cortisone, XI, an important hormone of. known utility.

EXAMPLE I Degradation of II-keto diosgenin acetate.In a 250 ml. thick glass bottle fitted with a wired-on, gas-tight,

ground-glass stopper were placed 14.5 g. of ll-keto dilog e=3.93. The mother liquors from this preparation were also used since they gave crystalline epoxide when treated as in Example 2. The total yield of crystalline product was 55 mole percent.

Calcd. for C H O C, 74.56; H, 8.16. Found: C, 74.36; H, 8.33.

When the product, was crystallized from methanol a molecule of solvent was bound to each molecule of steroid by solvation.

EMMPLE II .ifi-acetoxy-l 6a,] 7a-epoxy-5-pregnene-H ,20 dine.A 5.95 g. sample of the preceding preparation was dissolved in 800 ml. of methanol at 10 C., ml. of 30% hydrogen peroxide and 2.3 m1. of 4 N sodium hydroxide were added and the mixture was stored overnight. A crystalline water-insoluble precipitate formed and was filtered off. The filtrate was diluted with an equal volume of water and a new crop crystals formed and were filtered off. The filtrate was neutralized with hydrochloric acid and was well-extracted with methylene chloride which was evaporated to give a glassy residue. All solids were combed and converted to acetates by dissolving in 30 ml. of pyridine and. ml. of acetic anhydride and heating 0.75 hour on the steambath. On dilution with water and isolation by ether extraction 5.1 g. of ethanol recrystallized product were obtained (84% yield). The product was freed of 100 mg. of an unidentified extremely insoluble material (M.P. 318) by solution in ethyl acetate, filtering and crystallizing by evaporation to dryness. The product melted from 205206 C. forming dense polyhedra undergoing transition on the Kofler block to refractile, tetragonal prisms, [a] =+14.8.

Calcd. for C H O C, 71.48; H, 7.82. Found: C, 71.46; H, 8.08.

Saponification with 5% methanolic potassium hydroxide gave 4.46 g. of 16a,17a-epoxy-3fi-hydroxy-S-pregnene- 11,20-dione, IV, M.P. 111 to about 114 when crystallized from ethanol. Perhaps the molecule thus crystallized is solvated but the lower indicated melting temperature is characteristic.

Calcd. for C H o C, 73.22; H, 819. Found: C, 73.98; H, 8.01.

EXAMPLE HI 33,1Zu-dihydrOxy-S-pregnene-l],20-dione.To a. solution of 2.22 g. of 16a,l7a-epoxy-3fi-hydroxy-5-pregnene- 11,20-dione, IV, in 22 ml. of acetic acid was added 4.3 ml. of a 40% solution of hydrogen bromide in acetic acid. After standing for 25 minutes the reaction mixture was poured into ml. of cold Water and the precipitated bromohydrine was filtered off and air dried. Ten grams of Raney nickel was heated with 100 ml. of refluxing acetone. Ten ml. of Water, two ml. of acetic acid, and the crude bromohydrin were added and stirring and heating under reflux was maintained for 4 hours. The acetone solution was decanted and evaporated to dryness in vacuo. Crystallization of the residue from methylene chloride and from ethylacetate gave 1.57 g. (71% yield) of 313,17a-dihydroxy-S-pregnene-l1,20-dione, V. The compound formed dense polyhedral crystals, M.P. 277278 C. after transition over 220 to lance forms [a] +6 (MeOH).

Calcd. for (2 113004: C, H, 8.73. 72.41; H, 8.69.

Found: C.

EXAMPLE IV EXAMPLE V 21-acet0xy-3B-formoxy-1 7a-hydroxy-5-pregnene-I1,20- dione.The preceding formate 1.253 g. (0.00334 mole) Was dissolved in 25 ml. of dry methylene chloride and the solution was treated with 13.32 ml. of a solution of bromine (0.00334 moles) in 13.32 ml. of methylene chloride. The volume was reduced by distillation in vacuo at 30; the solution was washed with 1% sodium hydrogen carbonate solution; and the solvents removed in vacuo. The residue' was dissolved in acetone, 25 ml. and 2 g. of sodium iodide were added. The mixture was let stand overnight and was then poured into a cold solution of 2 g. of sodium thiosulfate in 70 ml. of water. The steroid was filtered 011 and dried in vacuo at room temperature. The crude iodo compound was dissolved in 25 ml. of dry acetone, 2.5 g. of potassium acetate was added and the mixture was heated under reflux and with stirring for 18 hours. The reaction mixture was cooled, poured into water and the steroid was isolated by extraction with ether. Evaporation of the ether in vacuo gave a colorless solid foam. Chromatography of this material with chloroform elution gave only 540 mg. of the desired crystalline, 21 acetoxy-3fl-formoxy-17a-hydroxy-5-preg nene-11,20-dione, VII, M.P. 192.5-193.5, red melt, [d] +20.8, but the colorless glassy residues eluted just after the crystalline material gave 100 mg. of the 1712 acetoxyl derivative, VIII, when treated as in Example VI.

Calcd. for C H O C, 66.65; H, 7.46. Found: C, 66.41; H,.7144.

EXAMPLE VI :,21 diacetoxy 319 formoxy 5 pregnene II, 20-dione.-The preceding compound, 99 mg., in 0.71 ml.

of acetic anhydride was treated with 31.4 mg. of p-toluene sulfonic acid at room temperature overnight. On decomposing with water an amorphous solid was obtained which on chromatography on Florisil gave 80 mg. of crystallizable material. The earlier benzene-eluted 17a, 21 diacetoxy 35 formoxy 5 pregnene 11,20-dione, VIII, [a] =+40 melts with decomposition from 228 to 229, occasionally from 233 to 235, and shows no hydroxyl band in the infrared spectrum, a broad multiple ketonic band and a series of ester bands at 1237, 1250, and 1260 cmf The chloroform eluate gave 17a,21- diacetoxy-3B-hydroxy-5-pregnene-11,20-dione, IX, M.P. 203-205 C., [a] =+83 showing infrared hydroxyl bands at 3410 and 3500 cm? (KBr disc), broad ketone bands centered at 1705 and 1731 cm? and a strong, sharp ester band centered at 1258 cm. with a small band at 124-5 cmf Non-crystallizable mother liquor residues were saved and carried through the Oppenauer oxidation reaction indicated in Example 7.

Compound VIII, calcd. for C H O C, 65.80; H, 7.22. Found: C, 65.50; H, 7.21.

Compound IX, calcd. for C H O C, 67.24; H, 7.68. Found: C, 67.02; H, 7.60.

EXAMPLE VII Corrisone 17a,21-diacetate and cortisone.Eight hundred milligrams of the uncrystallized mother liquor residues from Example 6 consisting essentially of a mixture of the 3-hydroxy and 3-formoxyl compounds were dissolved in 25 ml. of dry toluene. Eight ml. of cyclohexanone and 840 mg. of aluminum isopropoxide were added and the mixture was refluxed for 0.75 hour, cooled and water was added. The contents of the flask were heated until organic solvents were lost, and the gummy solid was collected by extraction with ether. Evaporation of the ether in vacuo and crystallization of the residue from methanol gave 400 mg. of cortisone, 1704,21- diacetate, X, M.P. 220-221",

ll??? 238 u e=35,000, identical with an authentic specimen. Hydrolysis of cortisone diacetate in 5% sodium hydroxide in methanol gave an 80% yield of cortisone, XI, identical with an authentic specimen.

EXAMPLE VIII Two hundred milligrams of crystalline, 17u,21-diacetoxy 3B-formoxy-5-pregnene-l1,20-dione, VIII, in 20 m1. of dry toluene, 300 mg. aluminum isopropoxide and 2 m1. of cyclohexanone were refluxed for minutes. Water, 100 ml, was added and the two-phase mixture was boiled until all organic solvents had been carried ofl in the vapors. The residue was collected as a pasty mass by decantation of the water. Crystallization from methanol gave a yield of cortisone, 17a,-21diacetate, X.

We claim:

1. 3B,17a-dihydroxy-5-pregnene-11,20-dione.

2. 3p formoxy 17a hydroxy 5 pregnene 11,20- dione.

3. 21 acetoxy 3,8 fonnoxy 17a hydroxy 5- pregnene- 1 1,20-dione.

4. 17a,21 diacetoxy 3p formoxy 5 pregnene- 11,20-dione.

5. 17a,21 diacetoxy 3,8 hydroxy 5 pregnene- 11,20-dione.

References Cited in the file of this patent .UNITED STATES PATENTS 2,596,563 Kaufmann May 13, 1952 2,667,498 Julian Ian. 26, 1954 2,668,816 Miescher Feb. 9, 1954- 2,684,364 Jones July 20, 1954 2,686,181 Julian Aug. 10, 1954 2,787,623 Gebert Apr. 2, 1957 2,805,230 Stork Sept. 3, 1957 2,857,404 Gash Oct. 21, 1958 2,874,172 Herzog et a1 Feb. 17, 1959 2,883,403 Rothman et al. Apr. 21, 1959 OTHER REFERENCES Djerassi: Chem. Abstracts, 1955, p. 7585, vol. 49. Wall et al.: J.A.C.S., vol. 77, pages 5665-68 (1955). Ringold et al.: J. Am. Chem. 800., 78, 816-819 (1956). 

1. 3B,17A-DIHYDROXY-5-PREGNENE-11,20-DIONE. 